Neuroprotective, neurotherapeutic, and neurometabolic effects of carbon monoxide

Vicki L Mahan

doi:10.1186/2045-9912-2-32

Abstract

Studies in animal models show that the primary mechanism by which heme-oxygenases impart beneficial effects is due to the gaseous molecule carbon monoxide (CO). Produced in humans mainly by the catabolism of heme by heme-oxygenase, CO is a neurotransmitter important for multiple neurologic functions and affects several intracellular pathways as a regulatory molecule. Exogenous administration of inhaled CO or carbon monoxide releasing molecules (CORM’s) impart similar neurophysiological responses as the endogenous gas. Its’ involvement in important neuronal functions suggests that regulation of CO synthesis and biochemical properties may be clinically relevant to neuroprotection and the key may be a change in metabolic substrate from glucose to lactate. Currently, the drug is under development as a therapeutic agent and safety studies in humans evaluating the safety and tolerability of inhaled doses of CO show no clinically important abnormalities, effects, or changes over time in laboratory safety variables. As an important therapeutic option, inhaled CO has entered clinical trials and its clinical role as a neuroprotective and neurotherapeutic agent has been suggested. In this article, we review the neuroprotective effects of endogenous CO and discuss exogenous CO as a neuroprotective and neurotherapeutic agent.

Highlights

carbon monoxide (CO) is critical in the brain for a host of functions
In our recent report we found that piglets preconditioned with inhaled CO had less apoptosis in the neocortex/striatum and hippocampus after cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA)
Studies in humans performed by INO Therapeutics LLC evaluated the safety and tolerability of inhaled single doses of carbon monoxide when administered as an inhaled gas for approximately 1 hour to healthy males

Summary

Introduction

CO is critical in the brain for a host of functions. Involvement of carbon monoxide (CO) in several aspects suggests that agents affecting the synthesis, transactions, and disposition of the gas have clinical relevance to neuroprotection [1,2]. Production and neuroprotective effects of endogenous carbon monoxide Endogenous formation of neuronal CO is dependent on the expression of brain heme oxygenases. Exogenous CO may result in a change in metabolic substrate in the brain and may define the role of exogenous CO in neurometabolism and, subsequent, neuroprotection. In a rat model of acute/severe hypoglycemia, Won and colleagues concluded that supplementation of glucose with lactate reduced neuronal death in the hippocampus and hypothesized that increasing brain lactate in this model offsets the decrease in NAD+ due to overactivation of PARP-1 by acting as an alternative energy substrate that can effectively bypass glycolysis and be fed directly to the citric acid cycle to maintain cellular ATP levels [56]. The authors proposed a compartmentalized CiMASH (Ca2+-induced limitation of the malate-aspartate shuttle) that defines pre- and post-

TYPE B

Findings

Conclusion